Involvement of RAGE in isoflurane-induced neuronal apoptosis

Abstract

Anesthetics, including isoflurane, have been demonstrated to induce apoptotic neurodegeneration when administered during neurodevelopment. There is inadequate clinical data to conclude whether anesthetics induce neurotoxicity in the developing human brain. The mechanism behind anesthesia induced neurotoxic effects is still unclear. Isoflurane has been reported to cause neurotoxicity and neurocognitive impairments in neonatal rats exposed to this gas. Previous reports suggest elevated levels of S100B after anesthesia and brain trauma. The receptor for advanced glycation end products (RAGE) is the only known cell surface receptor for S100B and expressed in the brain. RAGE activation in neurons has also been shown to lead to apoptosis and neurodegeneration. Our research investigates the hypothesis that anesthesia leads to RAGE activation and subsequently to neuronal apoptosis. In preliminary studies, we investigated the expression of RAGE in different areas of brain using immunohistochemical methods and found that RAGE was highly expressed in hippocampal region of brain. Apoptotic cells were detected in brain sections by colorimetric and fluorometric immunohistochemistry using cleaved caspase-3 as marker molecule. Immunofluorescence studies were used to investigate co-localizes RAGE expression and apoptotic cells and to identify cell types based on neuronal marker molecules. On the basis of our results, we demonstrate that RAGE may be involved in the neuronal apoptosis induced by isoflurane. Further investigation in this direction may help to develop therapeutic agents targeting RAGE that may be route for potential treatments to attenuate the post-anesthetic cognitive dysfunction in both young and aged patients.